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Recent Applications of Benzynes and Indolynes in Organic Synthesis

Recent Applications of Benzynes and Indolynes in Organic Synthesis. Trevor Mogg Nov.10, 2011. Outline. Part I - Benzyne Importance Discovery Properties Preparation Selected Reactions Total Synthesis Part II – Indolyne Reactivity and Applications. Importance of Benzynes.

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Recent Applications of Benzynes and Indolynes in Organic Synthesis

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  1. Recent Applications of Benzynes and Indolynes in Organic Synthesis Trevor Mogg Nov.10, 2011

  2. Outline • Part I - Benzyne • Importance • Discovery • Properties • Preparation • Selected Reactions • Total Synthesis • Part II – Indolyne • Reactivity and Applications

  3. Importance of Benzynes • Benzynes unique, highly reactive intermediate • Useful to create molecules • Traditional methods of preparation use harsh conditions or dangerous precursors • High reactivity requires careful selection of reaction conditions, substrate • Mild method of preparation allows more flexibility • Over last decade, new reactions of benzynes developed • Mild method of preparation extended to generate heteroaromaticindolynes • Useful for preparing biologically active molecules

  4. Discovery • First Evidence by Roberts (1953) • Trapping by Wittig (1956) = 14C via Roberts et al, JACS, 75, 3290 (1953). G. Wittig and L.Pohmer, Chem. Ber., 89, 1334 (1956).

  5. Benzynes • Belong to family of intermediates known as arynes • Di-radical, aromatic, highly reactive species • Properly called didehydrobenzenes – ortho, meta, para • Two non-bonding orbitals outside ring, perpendicular to p system, two electrons between them ortho para meta Roberto Sanz, Org. Prep. Proced. Int., 40 (3), 215-291 (2008). Sander et al, Angew Chem. Int. Ed., 2003, p502.

  6. Ortho-Benzyne • Reduced overlap of orbitals gives weak p bond • Better described as strained alkyne • Low-lying LUMO – Electrophilic • Readily undergoes pericyclic reactions, nucleophilic addition • Reacts with nucleophiles not normally reactive towards alkynes K.N. Houk et al, Tet. Lett., 35, 3237 (1979). Sander et al, Angew Chem. Int. Ed., 2003, p502. Roberto Sanz, Org. Prep. Proced. Int., 40 (3), 215-291 (2008). http://www.bama.ua.edu/~blacksto/CH435_CH531/home.html. Accessed Oct.20, 2011

  7. Preparing Benzyne Roberto Sanz, Org. Prep. Proced. Int., 40 (3), 215-291 (2008).

  8. Less Common Methods Cation Fragmentation -2 N2 Radicals Zwitterion *EXPLOSIVE* L. Friedman et al, Org.Synth., 48, 12 (1968). Jones, J.Org.Chem. ,1971, p1536. R.W. Franck et al, JACS, 1968, p.5814. Rees et al, J. Chem. Soc., 1969, p742.

  9. Aryl Anions • Ortho-metalation/elimination • Metal-halogen exchange/elimination • Fluoride induced elimination • Milder base than above methods, better functional group tolerance Durst et al, Org. Lett., Vol. 1, No.12, 1973 (1999). Suzuki et al, Tet. Lett., Vol.32, No.46, 6735 (1991). Kobayashi et al, Chem. Lett., 1211 (1983).

  10. TMS Triflate • Available from Aldrich – $176 for 5 grams • Several published methods of preparation • One example uses 2-bromophenol as starting material 65% 80% 92% Kobayashi et al, Chem. Lett., 1211 (1983). Guitian et al, Synthesis, 2002, p.1454.

  11. Regioselectivity • Controlled by Steric and Electronic Effects Roberto Sanz, Org. Prep. Proced. Int., 40 (3), 215-291 (2008). K. Suzuki, Tet. Lett., 1991, Vol.32, p6735.

  12. Selected Reactions of Benzyne • Nucleophilic Addition • Pericyclic Reactions • [2+2] • [3+2] • [4+2] • Ene • Palladium Catalyzed Reactions

  13. Nucleophilic Addition 53% Buchwald et al, J.Org.Chem., 2000, p5334. 65% Barrett et al, JACS, 2006, Vol. 128, p14042

  14. Nucleophilic Addition Hiyama et al, Angew. Chem. Int. Ed., 2002, p.3247. 66% Greaney et al, Angew. Chem. Int. Ed., 2009, p5199. 65%

  15. Acyl Alkylation of Benzyne • Insertion of Benzyne into C-C bond + 42% 53% Via Stoltz et al, JACS, 2005, p5341.

  16. Acyl Alkylation of Benzyne • Improved selectivity by removal of a-substituent • Ring Expansion 90% 50% Stoltz et al, JACS, 2005, p5341.

  17. Pericyclic Reactions • Benzyne low lying LUMO; readily undergoes pericyclic • Cyclic dienes locked in flat s-cis conformation give [4+2] (e.g. furan, cyclopentadiene) • Some substrates undergo competing [4+2], [2+2], and ene processes Waali, J. Org. Chem., 1975, p1355. Huisgen,Tet. Lett., 1963, p1017. Crews, J. Org. Chem., 1973, p522. Braun, J. Org. Chem., 1970, p1208.

  18. [2+2] Additions 44% Liebeskind et al, J.Org.Chem., 1989, p1435. Hsung et al, Org. Lett., 2009, p.3666. 95%

  19. [3+2] Additions + Larock et al, J.Org.Chem., 2010, p7381 58% R = CH2CO2Et, Aryl, Cinnamyl Larock et al, Org. Lett., 2008, p2409.

  20. [4+2] Additions K. Suzuki et al, JACS, Vol.114, No.9, p.3568 (1992). + 68% Olofson et al, J.Org.Chem., 1992, p.7122.

  21. Intramolecular [4+2] and Ene Additions Danheiser et al, Org.Lett., 2005, p3917. Lautens et al, JACS, 2011, Vol.133, p.14200.

  22. [4+2] - Dihydronapthalenes + 48% er > 19:1 First EnantioselectiveAryne Diels Alder Reaction Lautens et al, JACS, 2005, Vol. 127 p15028.

  23. Palladium Catalyzed Cyclizations Yamamoto et al, Angew. Chem. Int. Ed., 2000, p173. Phenanthrene 69% + 5eq. Larock et al, J. Org. Chem., 2008, p6679. Fluoren-9-one 75%

  24. Palladium p-Allyl Reactions R1 = aryl, allenyl, alkynyl Cheng et al, Org Lett, 2005, p2921. Cheng et al, Org. Lett., 2004, p2821. Cheng et al, Synthesis, 2005, p1693. Yields 66-93% R2 = aryl, alkyl Cheng et al, Angew Chem. Int. Ed, 2009, p391. Yields 59-92%

  25. Outline • Part I - Benzyne • Importance • Discovery • Properties • Preparation • Selected Reactions • Total Synthesis • Part II – Indolyne • Reactivity and Applications

  26. Total Synthesis: (-)–Quinocarcin • Isolated from Streptomycesmelunovinuceus • Antitumor, antibiotic properties • Brian Stoltz’s Group, California Institute of Technology • Shortest total synthesis to date (11 steps) • Formed by formal [4+2] annulation of benzyne (-) - Quinocarcin Stoltz et al, JACS, 2008, vol.130, p17270. Zhu, JACS, 2008, Vol.130, p7148.

  27. Enamide Synthesis 74%, 2 steps 69% 93% Stoltz et al, JACS, 2003 p.15000. Stoltz et al, JACS, 2008, p17270. Karmas et al, JACS, 1952 p1580.

  28. [4+2] Annulation 60% Stoltz et al, JACS, 2008, vol.130, p1558. Stoltz et al, JACS, 2008, vol.130, p17270.

  29. Completion of (-)-Quinocarcin 99% 80% (-)-Quinocarcin 81%, 2 steps Stoltz et al, JACS, 2008, vol.130, p17270.

  30. Outline • Part I - Benzyne • Importance • Discovery • Properties • Preparation • Selected Reactions • Total Synthesis • Part II – Indolyne • Reactivity and Applications

  31. Part II: Indolynes • A heteroaromaticaryne • First indolyne from Igolen and co-workers in1967; nothing in literature until 2007 • Keith Buszek and co-workers prepared and trapped three indolynes with furan • Useful to synthesize compounds containing indole rings -> biologically active compounds • Further studies by Buszek and Garg Labs 5,6-Indolyne 4,5-Indolyne 6,7-Indolyne Reinecke, Tetrahedron, 1982, p427. Buszek et al, Org.Lett., 2007, Vol.9, No.21, p.4135 Igolen et al, ComptesRendus des Seances de l’Academie des Sciences, Serie C: Sciences Chimique, Vol. 265, Iss.2, p.110, 1967.

  32. Indole TMS Triflate • To study reactivity of 4,5-Indolyne, TMS Triflate was prepared 88% Garg et al, JACS, 2010, vol.132, p17933. Garg et al, Org. Lett., 2009, Vol.11, No.4, p1007.

  33. Indolyne Reactivity Patterns Nucleophile C5 : C4 : 12.5 1 : 3 1 : 3.3 1 K. Houk, N. Garg et al, JACS, 2010, Vol.132, p.1267.

  34. Unsymmetrical Aryne Distortions • Pre-distorted ring gives C5 larger internal angle, orbital has electropositive “p” character • C4 smaller internal angle, orbital has more electronegative “s” character • Attack occurs at flat, electropositive end, relieves ring distortion Aniline Addition C3a C3a C4 C5 C4 C3a C5 K. Houk, N. Garg et al, JACS, 2010, Vol.132, p1267.

  35. Regioselectivity Reversal • 4,5-Indolyne with Br atom, reversed selectivity C4 C4 C5 C5 Garg et al, JACS, 2011, Vol.133, p.3832.

  36. Indolactam V • Activator of protein kinase C • Synthesis by Neil Garg’s Group • Demonstrates reversal of normal indolyne selectivity by introducing Br atom • C-N bond formed by nucleophilic attack Indolactam V Garg et al, JACS, 2011, Vol.133, 3822.

  37. Indolyne Addition 62% (<5% other regioisomer) Garg et al, JACS, 2011, Vol.133, 3822. K.Houk, N.Garg et al, JACS, 2010, vol.132, p17933.

  38. Completion of Indolactam V Yield Not Given 3:1 Mixture of Diastereomers Indolactam V Garg et al, JACS, 2011, Vol.133, 3822. Nakatsuka et al, Agric. Biol. Chem., 1989, vol.53, p2257.

  39. (-)-N-methylwelwitindolinone C Isothiocyanate • Isolated from blue-green algae Hapalosiphonwelwitschii and Westiellaintricata in 1994 • Reverses P-glycoprotein mediated multiple drug resistance to variety of anticancer drugs in human cancer cell lines • Promising for treating drug-resistant tumors • First total synthesis of this compound by Neil Garg’s Group • Intramolecularcyclization via nucleophilic attack on indolyne (-)-N-methylwelwitindolinone C Isothiocyanate Garg et al, JACS, 2011, Vol.133 (40), p15797. Moore et al, JACS, 1994, Vol.116, p9935.

  40. Retrosynthesis IndolyneCyclization Garg et al, JACS, 2011, Vol.133 (40), p15797.

  41. Indole Substitution S-Carvone Garg et al, JACS, 2011, Vol.133 (40), p15797. Natsume et al, Chem. Pharm. Bull., 1994, Vol.42, p1393. Wang et al, Synlett., 2003, p.2377.

  42. IndolyneCyclization + 46% 2.5 : 1 Garg et al, JACS, 2011, Vol.133 (40), p15797.

  43. Nitrene Insertion Garg et al, JACS, 2011, Vol.133 (40), p15797.

  44. Completion of Target (-)-N-methylwelwitindolinone C Isothiocyanate Garg et al, JACS, 2011, Vol.133 (40), p15797.

  45. Summary • Benzyne readily undergoes nucleophilic, pericyclic, palladium catalyzed reactions • Mild conditions allows greater variety of substrates to be used, new reactions • Benzyne has been used to complete total synthesis of (-)-Quinocarcin • Regioselectivity of Indolyne explained through models • Reversal of Indolyneregioselectivity demonstrated through synthesis of Indolactam V • Indolyne has been used to complete first total synthesis of N-methylwelwitindolinone C isothiocyanate

  46. Acknowledgements • Dr. Tony Durst • Durst Lab Members • Chemaphor Members

  47. EXTRA SLIDES • Prep of starting material in N-Methylwelwetindolinone C Isothiocyanate Synthesis

  48. Indolynes • Prepared three indolynes Buszek et al, Org.Lett., 2007, Vol.9, No.21, p.4135

  49. TMS Triflate Guitian et al, JACS, 1999, p5827.

  50. Bromoindole TMS Triflate Synthesis Garg et al, JACS, 2011, Vol.133, 3822. Garg et al, JACS, 2010, vol.132, p17933.

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